The prevalence of latent tuberculosis infection in patients with chronic kidney disease: A systematic review and meta-analysis

Objective To estimate the prevalence of latent tuberculosis infection (LTBI) in chronic kidney disease (CKD) patients. Methods This study was conducted following the PRISMA guidelines. We identified, 3694 studies from the whole search, and 59 studies were included. Each study's quality was assessed using JBI checklist. We employed STATA version 17 for statistical analysis. We assessed heterogeneity using I2 heterogeneity test. Publication bias was assessed using funnel plot and Egger's test. We estimated the pooled LTBI prevalence in CKD patients along with 95%CI. Results The pooled prevalence of LTBI among CKD patients using data collected from 53 studies having 12,772 patients was 30.2% (95%CI; 25.5, 34.8). The pooled prevalence among pre-dialysis, hemodialysis, peritoneal dialysis, and renal transplanted patients was 17.8% (95%CI; 3.3, 32.4), 34.8% (95%CI; 29.1, 40.5), 25% (95%CI; 11, 38), and 16% (95%CI; 7, 25), respectively. The pooled prevalence of LTBI stratified by the laboratory screening methods was 25.3% (95%CI: 20.3–30.3) using TST, 28.0% (95%CI; 23.9–32.0) using QFT, and 32.6%, (95%CI: 23.7–41.5) using T-SPOT. Conclusion There is high prevalence of LTBI among CKD patients mainly in patients on dialysis. Thus, early diagnosis and treatment of LTBI in CKD patients should be performed to prevent active TB in CKD patients. PROSPERO registration number: CRD42022372441.


Introduction
Tuberculosis (TB) continues to be a major public health issue across the globe. It is the second leading cause of mortality among Abbreviations: CKD, Chronic Kidney Disease; IGRA, Interferon Gamma Release Assay; LTBI, Latent Tuberculosis Infection; TB, Tuberculosis; TST, Tuberculin Skin Test.
infectious diseases next to COVID-19 [1]. Countries are committed to control and prevent TB by developing and adapting different strategies and measurable targets. The World Health Organization (WHO) developed the END-TB strategy that aims to reduce the incidence of TB to less than 10 per 100,000 populations by 2035 [2]. However, achieving this ambitious objective may be challenging unless a specific intervention approach that addresses the burden in a high-risk population is created and implemented. For example, specific groups of people, such as those with chronic kidney disease (CKD), are at a higher risk of contracting TB than the overall population, necessitating a focused intervention [3]. According to our recent global systematic review and meta-analysis, the incidence of TB in CKD patients was 3718/100,000 population [4]. A pooled estimate revealed that patients on dialysis had 3.6 times the risk to develop TB compared to the general population [5]. Currently, the incidence of CKD is rising in developing countries where TB is also endemic which may halt the TB prevention and control efforts to achieve the END-TB strategy [6].
Early detection and treatment of latent tuberculosis infection (LTBI) among groups of people with weakened immune systems, such as CKD patients, is critical for preventing the development of active TB. In addition, dialysis patients frequently travel to health facilities for medical care, which may increase the risk of infection with Mycobacterium tuberculosis [7]. When compared to healthy adults, these patients have a 10-25 fold increased chance of risk of reactivating LTBI [7]. The WHO recommends that persons undergoing dialysis or preparing for an organ transplant be tested and treated for LTBI [8]. There have been studies undertaken in different countries and settings to determine the prevalence of LTBI in CKD patients [7,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The prevalence of LTBI in CKD patients has been found to range from 6% [24,25] to 82% [23]. The systematic reviews were primarily concerned with comparing the performance of diagnostic tools for detecting of LTBI in dialysis patients [26][27][28]. However, there is limited data that reported the global, and regional prevalence of LTBI among CKD patients in general and across different categories. A global data that comprehensively assessed the burden of LTBI in CKD patients can be an essential input for policy development and guidance to boost the effort for TB prevention and control, as well to improve the quality of life for this population group. Thus, this study aimed to estimate the global pooled prevalence of LTBI among patients with CKD.

Protocol registration
The protocol for this systematic review and meta-analysis study is registered on the International Prospective Register of Systematic Reviews (PROSPERO) with a registration number CRD42022372441.

Article search strategy and selection procedure
This systematic review and meta-analysis study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [29]. Two independent investigators (AA, ZWB) conducted article searching, and the third investigator (GD) resolved the inconsistencies. Both electronic databases and grey literature sources were searched for previously published studies that A. Alemu et al. reported LTBI among patients with any types of CKDs. We searched articles published in English language until November 21, 2022. PubMed, Global Index Medicus, Informit, Joanna Briggs Institute EBP Database (including OVID), and Global Health were among the electronic databases used. Whereas the grey literature sources were Google, and Google Scholar. The searching was carried out using the key terms in conjunction with the Boolean operators AND and OR. The keywords used in the current study includes; latent tuberculosis, chronic kidney disease patient, renal failure, dialysis, hemodialysis, peritoneal dialysis, renal-transplant, pre-renal transplant, and pre-dialysis. All of the articles identified during the entire search were exported to Endnote X8 citation manager. We have followed a stepwise approach to select the studies included in the final data-analysis. In the primary step, duplicates were removed and then the articles were screened by title and abstract. All the articles that passed the above stage were eligible for full-text screening and those that passed the full-text assessment were included in the final data analysis (Fig. 1) (Appendix).

PICOS criteria
Participants: Patients with chronic kidney disease. Intervention: Not applicable. Comparator: Not applicable. Outcome: Latent TB infection. Study design: Observational studies. Study setting: Any setting in any country across the globe.

Inclusion and exclusion criteria
Studies that assessed prevalence of LTBI among different categories of CKD patients (pre-dialysis, hemodialysis, peritoneal dialysis, or renal transplanted) were included in the study. Review studies, incomplete studies and articles with different outcomes were excluded.

Data extraction
We extracted data from all studies included in the current systematic review and meta-analysis using the 2016 Microsoft Excel Spreadsheet. Two investigators (GS, EG) extracted data independently, and the inconsistencies were resolved through discussion and consensus was reached with the guidance of the third author (AA). The extracted data included; first author name, publication year, country, data collection period, study design, age group, type of CKD patients included, laboratory screening method, sample size, and number of patients who had LTBI. In addition to the above variables, the studies were categorized based on continent, WHO regional classification, and country TB burden category (Table 1).

Outcome
The primary outcome of this study was detection of LTBI among CKD patients with any category including pre-dialysis, hemodialysis, peritoneal dialysis, and renal transplant. The included studies used different laboratory screening methods alone or in combination for screening of LTBI in CDK patients; Tuberculin Skin Test (TST), QFT (QuantiFERON®-TB Gold), T-SPOT, and ELISPOT (enzyme-linked immunospot). The TST result was considered positive when the cut-off induration was ≥10 mm. From studies that employed a two-step TST, only the baseline results were taken to avoid a boosting phenomenon.

Quality assessment
Two independent investigators (AA, GS) assessed the quality and validity of individual studies included in this study using the Joanna Brigg's Institute critical appraisal tool [30]. The inconsistencies that arose between the two authors were resolved by the third investigator (ZWB). The JBI tool for prevalence study was used to assess the study's quality. Each question on the checklist was scored equally, and their total was calculated out of 100%. We classified the quality score as low, medium, and high quality when the score was <60%, 60-80%, and >80%, respectively.

Data synthesis and analysis
The data that were summarized in the 2016 Microsoft Excel Spreadsheet were exported to STATA version 17 for statistical analysis. The pooled prevalence of LTBI among CKD patients was estimated along with 95%CI. Sub-group analysis was performed based on CKD categories, LTBI laboratory screening methods, WHO regional classification, continent, country's income level, publication year, and TB burden category. We have presented the pooled estimates using forest plot. The presence of heterogeneity among studies was assessed using I 2 heterogeneity test where I 2 >50% was considered as the presence of substantial heterogeneity [31,32]. We have used the random-effect model considering the presence of substantial heterogeneity. We assessed the presence of publication bias through the visual inspection of the funnel plot and the statistical significance of the Egger's regression test (P < 0.05) [33,34]. A trim-and fill analysis was done to adjust the publication bias [35].

Table 1
Characteristics of individual studies on the prevalence of latent tuberculosis among patients with chronic kidney disease, included in the current systematic review and meta-analysis.

Study characteristics
From the whole search, 5316 studies were identified and 854 duplicates were removed. Title and abstract screening was conducted for the 4462 studies and 4388 were excluded. Then, the remaining 74 studies were assessed for full text and 59 studies were included in the final analysis. While the remaining 15 studies were excluded due to different reasons (review articles, incomplete studies, articles   with different outcomes) (Fig. 1) (Appendix).
The studies were conducted in 18 countries from four continents. The highest number of studies were from Asia (39 studies) followed by North America (8 studies), South America (6 studies), and Europe (5 studies). The least number of study was from Africa with only one study conducted in Egypt. Based on the WHO regional classifications, the highest number of studies were from the West Pacific Region (WPR) with 16 studies followed by the European Region (EUR) (15 studies), the Region of Americans (AMR) (14 studies), Eastern Mediterranean Region (EMR) (9 studies), and South East Asian Region (SEAR) (5 studies). No study was reported from the WHO African Region (AFR). Specifically, the most frequent studies were from Turkeye (10 studies) followed by Taiwan (9 studies), South Korea (5 studies), Canada (5 studies), and Brazil (5 studies). The other studies were reported from Saudi Arabia, United States, India, Iran, Indonesia, Japan, Switzerland, Belgium, Egypt, Germany, Iraq, Mexico, and United Kingdom. Based on the World Bank income classification, 6, 20, and 27 studies were reported from lower middle income, upper middle income and high income countries, respectively.
Based on publication year, 22, 17, and 20 studies were published from 1998 to 2010, from 2011 to 2015 and from 2016 to 2022. Based on the 2021 global TB report, 10 studies were reported from high TB burden countries while the remaining 49 studies were reported from countries that were not included in the high TB burden country list. The majority of the studies (43 studies) were conducted using a cross-sectional study design (Table 1).
Different laboratory diagnostic methods such as TST and IGRA (QFT, T-SPOT and ELISPOT) were used to detect LTBI in CKD patients. The IGRA method was used in 36 studies where QFT, T-SPOT, and ELISPOT were used in 29, 11 and 1 studies, respectively. However, the type of IGRA methods were not specified in three studies. Tuberculin skin test was used in 47 studies. These diagnostic methods were used alone or in different combinations (Table 1).

Pooled prevalence of latent tuberculosis among patients with chronic kidney disease
We have extracted data from 59 studies, but the pooled prevalence of LTBI among CKD patients was determined by using 53 studies. In the remaining six studies, the studies used two or more laboratory screening methods and data was available for the specific method, but we were unable to get the overall LTBI prevalence in combination of the laboratory methods. The highest sample size was 1790 [13], while the lowest sample size was 30 [36]. The highest prevalence was 82% from Iran [23], and the lowest prevalence 6% from Canada [24] and from Japan [25]. When pooled together, 3219 CKD patients had LTBI from 12,772 patients. Based on the random effect model, the pooled prevalence of LTBI among CKD patients was estimated as 30.2% (95%CI; 25.5, 34.8, I 2 ; 97.82%) (Fig. 2). There was high heterogeneity among studies, and publication bias was revealed by funnel plot (Fig. 3) and Egger's regression test (P = 0.0006). However, after the trim-and-fill analysis, there was no change in the pooled estimate (Fig. 2) (Table 2).

Pooled prevalence of latent tuberculosis per laboratory diagnostic method
We have performed a sub-group analysis, using the laboratory diagnostic method used to detect LTBI in CKD patients. Accordingly, TST, QFT, T-SPOT, ELISPOT, and unspecified IGRA were used. Tuberculin skin test was used by 47 studies, where the highest prevalence was 82% [23] and the lowest prevalence was 3% [37,38]. A total of 8208 CKD patients were screened by TST and 1966 were found to have LTBI. Based on the random effect model, the pooled prevalence of LTBI among CKD patients screened by TST was 25.3% (95%CI; 20.3%, 30.3%, I 2 ; 97.71%) (Fig. 4). The Egger's regression test (P = 0.002) revealed the presence of publication bias (Appendix). However, there is no change in the pooled prevalence after the trim and fill analysis. The QFT test was used in 29 studies where the largest and the smallest LTBI prevalence among CKD patients detected by QFT were 54% [39], and 6% [25], respectively. From 4821 CKD patients screened for LTBI using QFT, 1285 were found to have LTBI that gave a pooled prevalence of 28.0% (95%CI; 23.9, 32.0, I 2; 90.83%) (Fig. 5). The presence of publication bias was revealed by the asymmetry of the funnel plot and the statistical significance of the Egger's regression test (P = 0.0003) (Appendix). After the trim and fill analysis, the pooled estimate became 25.4% (95%CI; 21.1%, 29.8%). The other laboratory method used to detect LTBI in CKD patients was T-SPOT that is used by 13 studies. Based on this method, the smallest and the highest LTBI prevalence was found to be 4% [25] and 58% [40], respectively. Among 1412 CKD patients screened for LTBI using T-SPOT, 595 patients were found to have LTBI. Based on the random effect model, the pooled prevalence of LTBI in CKD patients screened by T-SPOT was 32.6% (95% CI; 23.7, 41.5, I 2 ; 97.53%) (Fig. 6). Based on the Egger's regression test there is no publication bias (P = 0.306) (Appendix). Since there is only one study that used ELISPOT, it was difficult to estimate the pooled prevalence (Table 2).

Prevalence of latent tuberculosis across categories of chronic kidney disease
In this study, we have performed a sub-group analysis to estimate the pooled prevalence of LTBI based on the category of CKD such that pre-dialysis, hemodialysis, peritoneal dialysis and post-renal transplantation. Specifically, 39, 6, 5, and 3 studies assessed the prevalence of LTBI in hemodialysis, post-renal transplantation, peritoneal dialysis and pre-dialysis patients, respectively. Among 432 pre-dialysis patients, 61 were found to have LTBI that gave a pooled LTBI prevalence of 17.8% (95%CI; 3.3, 32.4, I 2 ; 90.61%) (Fig. 7). In hemodialysis patients, the smallest prevalence of LTBI was 9% [12], while the highest prevalence was 82% [23]. A total of 7534 hemodialysis patients were screened for LTBI and 2396 were found to have LTBI with a pooled LTBI prevalence of 34.8% (95%CI; 29.1, 40.5, I 2 ; 96.87%) (Fig. 8). The Egger's regression test was on the borderline (P = 0.049) that revealed the presence of publication bias. However, after the trim and fill analysis, there was no change in the pooled estimate. The third group of patients were those on peritoneal dialysis. We have estimated the pooled prevalence using four studies having 60 LTBI cases among 253 patients that gives a pooled prevalence of 25% (95%CI; 11, 38, I 2 ; 83.48%) (Fig. 9). The last group of CKD patients were those who had undergone renal transplantation. The pooled prevalence of LTBI among CKD patients who underwent transplantation was estimated using six studies that comprises 1100 renal transplanted patients. LTBI was detected in 159 patients that gave a pooled LTBI prevalence of 16% (95%CI; 7, 25, I 2 ; 94.26%) (Fig. 10) (Table 2). We conducted a meta-regression analysis to assess the effect of sample size and publication year on the heterogeneity among studies. The multivariate meta-regression model revealed that sample size (P = 0.064) and publication year (0.553) did not significantly predicted heterogeneity among studies. However, this model only explains 4.58% of the heterogeneity (Table 3).

Discussion
In this study, we estimated the pooled prevalence of latent tuberculosis among patients with chronic kidney disease based on data collected from 53 studies that included 12,772 CKD patients. The study findings indicated that nearly one-third of CKD patients had LTBI with regional disparities. In addition, we conducted a sub-group analysis to estimate the pooled prevalence of LTBI based on the type of CKD, the laboratory diagnostic methods, continent, WHO regional classification, country's income level, publication year, and TB burden classification.
This study revealed that, 30% of CKD patients had LTBI, which is higher compared to the prevalence in the general population, where one-fourth of the global population is infected with TB [1]. In addition, this pooled estimate exceeds the global pooled estimate obtained among the general population, which was less than 25% [41]. This higher LTBI prevalence among CKD patients indicated that this group of population are at higher risk to develop active TB. This was corroborated in our recent meta-analysis, in which 3718/100, 000 CKD patients got TB during their follow-up period, substantially above the TB incidence in the general population [4]. This emphasizes the necessity of early and active screening, testing and treatment of LTBI in CKD patients in order to strengthen active TB prevention and control, which can improve the quality of life in this population. The outcomes of this study can be used to develop future guidelines and guidance. According to the WHO regional classification of countries, the highest pooled estimate was found in EUR (43%), followed by EMR (39%), SEAR (32%), WPR (21%), and AMR (19%). In a previous global meta-analysis study the decreasing order of the pooled prevalence of LTBI among the general population stratified per WHO regional classification was SEAR, AFR, EMR, WPR, AMR and EUR. Since we did not get studies from the WHO African region, we were unable to find the estimate the pooled estimate.  We also conducted a sub-group analysis based on publication year, and the study findings revealed that the pooled estimate is lower in studies published after 2016 (24%) compared to studies published between 1998 and 2010 (34%), and between 2011 and 2015 (34%). A global study [42] similarly found a modest reduction in the prevalence of LTBI. In addition, we have also estimated the pooled prevalence based on country's TB burden classification. The findings revealed that countries not included in the high TB burden countries had a relatively greater prevalence than their counterparts did.
The current study found that dialysis patients in general and hemodialysis patients in particular, had higher LTBI prevalence as compared to pre-dialysis and post-renal transplanted patients. Dialysis patients, particularly those on hemodialysis, are at increased risk of contracting Mycobacterium tuberculosis through person-to-person transmission since they travel frequently and spend lengthy periods in health facilities.
Besides, we have performed a sub-group analysis based on the laboratory diagnostic method used to diagnose LTBI in CKD patients. We found a relatively a higher pooled estimate in CKD patients diagnosed with IGRAs compared with TST. One possible reason might be the use of 10 mm cut-off in the TST. Likewise, this was reported by a previous global pooled estimate conducted in the general population [31]. In general, CKD patients suffer from multitude complications ranging from anemia, psychiatric diseases, cardiovascular complications, endocrine and metabolic abnormalities that needs to be given a focus to decrease high morbidity, mortality and poor quality of life [43][44][45].
Finally, the findings of this study should be interpreted by considering the following limitations. Primarily, under representation of CDKs from Africa in this review may have affected the global prevalence of LTBI in CDK patients. Second, the high heterogeneity among studies and the presence of publication bias may affect the true estimates. Lastly, since most of the original studies did not use specific cutoffs based on age and immunosuppression status of CKD patients, we did not perform analysis based on the specific cutoffs. However, we have performed stratified analysis that validated the current study findings.

Conclusion
This study identified higher prevalence of LTBI among CKD patients that needs attention of all concerned bodies to early detect and treat LTBI in this group of individual. There is disparities in the prevalence of LTBI per WHO regional classification, where CKD patients residing in the EUR, EMR and SEAR had relatively higher LTBI prevalence. In addition, dialysis patients mainly hemodialysis patients had higher LTBI prevalence compared to pre-dialysis and post-renal transplanted CKD patients. Besides, the prevalence of LTBI is higher in patients diagnosed with IGRA compared with those CKD patients diagnosed with TST. The findings in this study   indicate the need to give attention for the early diagnosis and treatment of LTBI in CKD patients. We recommended more studies from the African Region where TB is endemic and the prevalence of CKD is increasing.

Author contribution statement
Ayinalem Alemu: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Wrote the paper.

Data availability statement
Data included in article/supp. material/referenced in article.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.